Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray
Open accessAbstract
A multistep model for pancreatic adenocarcinoma has been proposed recently. In this model, well-defined, noninvasive ductal lesions are recognized as precursors of invasive cancer and have been classified under the nomenclature of pancreatic intraepithelial neoplasia, or PanIN. Increasing evidence suggests that PanINs represent true neoplasms of the pancreatic ductal epithelium, accumulating histologic and genetic abnormalities in their progression toward invasive cancer. We have constructed a tissue microarray containing 55 PanIN lesions of all histologic grades in order to perform a multicomponent analysis of the pancreatic adenocarcinoma progression model. The protein products of 14 genes encompassing a variety of functional classes, such as tumor suppressor genes (p53, Smad4/Dpc4), oncogenes (beta-catenin), cell cycle antigens (p16, cyclin D1), proliferation antigens (Ki-67, topoisomerase II alpha), and epithelial apomucins (MUC1, MUC2, MUC5), as well as "novel" genes described as differentially up-regulated in invasive pancreas cancer by global microarray expression analysis (mesothelin, prostate stem cell antigen, fascin, and 14-3-3varsigma), were analyzed by immunohistochemistry on the PanIN tissue microarray. Comparison of the results from the current study with previously published data performed on routine histologic sections of PanINs demonstrates that tissue microarrays are a valid platform for molecular analysis not only of invasive cancers but of precursor lesions as well. In addition, this study demonstrates that molecular abnormalities in PanINs are not random but can usually be stratified into "early" changes (e.g., expression of MUC5 and prostate stem antigen, or loss of p16), "intermediate" changes (e.g., expression of cyclin D1), and "late" changes (e.g., expression of p53, proliferation antigens, MUC1, mesothelin, and 14-3-3varsigma, or loss of Smad4/Dpc4). Understanding the molecular pathogenesis of precursor lesions of invasive pancreatic adenocarcinomas using a high-throughput tissue microarray-based approach is a valuable adjunct to designing rational strategies for early detection of this lethal neoplasm.
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A putative pathological progression model for PDAC, analogous to the colon adenoma-carcinoma model, was developed from early molecular profiling and histology.
“Early molecular profiling coupled with histology allowed for the development of a putative pathological progression model; analogous to the adenoma-carcinoma model in the colon23”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [23]
TP53 and SMAD4 alterations typically occur late in multistep progression, usually in high-grade lesions or cancer in both PanINs and IPMNs.
“The temporal appearance of these alterations during multistep progression suggests that TP53 and SMAD4 typically occur late, usually in the setting of high-grade lesions or cancer in both PanINs and IPMNs23,51.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [23]
About 40% of pancreatic ductal adenocarcinomas have both mutated TP53 and deleted ARF.
“For example, approximately 40% of pancreatic ductal adenocarcinomas have mutated TP53 and deleted ARF (Heinmoller, et al., 2000; Hustinx, et al., 2005; Maitra, et al., 2003).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Maitra, et al., 2003
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Genetics and biology of pancreatic ductal adenocarcinomaPreprint
Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N. M., & DePinho, R. A. (2006) · Genes & Development · doi:10.1101/gad.1415606 · Cited by 1,570 · see citing works
Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
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Self-citationPhenotype and Genotype of Pancreatic Cancer Cell Lines
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Maitra, A., & Hruban, R. H. (2008) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathmechdis.3.121806.154305 · Cited by 707 · see citing works
Self-citationMutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer
Morton, J. P., Timpson, P., Karim, S. A., Ridgway, R. A., Athineos, D., Doyle, B., Jamieson, N. B., Oien, K. A., Lowy, A. M., Brunton, V. G., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908428107 · Cited by 657 · see citing works
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KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma
Morris, J. P., Wang, S. C., & Hebrok, M. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2899 · Cited by 567 · see citing works
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Independence and reproducibility across microarray platforms
Larkin, J. E., Frank, B. C., Gavras, H. P., Sultana, R., & Quackenbush, J. F. (2005) · Nature Methods · doi:10.1038/nmeth757 · Cited by 420 · see citing works
Iacobuzio–Donahue, C. A., Ashfaq, R., Maitra, A., Adsay, V. N., Shen-Ong, G. L. C., Berg, K. D., Hollingsworth, M. A., Cameron, J. L., Yeo, C. J., Kern, S. E., et al. (2003) · PubMed · Cited by 415 · see citing works
Self-citationInfante, J. R., Matsubayashi, H., Sato, N., Tonascia, J., Klein, A. P., Riall, T. S., Yeo, C. J., Iacobuzio–Donahue, C. A., & Goggins, M. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.07.8824 · Cited by 403 · see citing works
Self-citationChiyomaru, T., Enokida, H., Tatarano, S., Kawahara, K., Uchida, Y., Nishiyama, K., Fujimura, L., Kikkawa, N., Seki, N., & Nakagawa, M. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605570 · Cited by 324 · see citing works
Stromal biology of pancreatic cancer
Chu, G. C., Kimmelman, A. C., Hezel, A. F., & DePinho, R. A. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21209 · Cited by 321 · see citing works
Hedgehog/Ras interactions regulate early stages of pancreatic cancerPreprint
di Magliano, M. P., Sekine, S., Ermilov, A. N., Ferris, J., Dlugosz, A. A., & Hebrok, M. (2006) · Genes & Development · doi:10.1101/gad.1470806 · Cited by 302 · see citing works
MicroRNA miR-155 is a biomarker of early pancreatic neoplasia
Habbe, N., Koorstra, J.-B. M., Mendell, J. T., Offerhaus, G. J. A., Ryu, J. K., Feldmann, G., Mullendore, M. E., Goggins, M., Hong, S., & Maitra, A. (2009) · Cancer Biology & Therapy · doi:10.4161/cbt.8.4.7338 · Cited by 296 · see citing works
Self-citationMino-Kenudson, M. A., Castillo, C. F.-D., Baba, Y., Valsangkar, N. P., Liss, A. S., Hsu, M., Correa‐Gallego, C., Ingkakul, T., Johnston, R. P., Turner, B. G., et al. (2011) · Gut · doi:10.1136/gut.2010.232272 · Cited by 292 · see citing works
Precursors to Invasive Pancreatic Cancer
Maitra, A., Fukushima, N., Takaori, K., & Hruban, R. H. (2005) · Advances in Anatomic Pathology · doi:10.1097/01.pap.0000155055.14238.25 · Cited by 290 · see citing works
Self-citationRoles of fascin in human carcinoma motility and signaling: Prospects for a novel biomarker?
Hashimoto, Y., Skacel, M., & Adams, J. C. (2005) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2005.05.004 · Cited by 275 · see citing works
Molecular genetics of pancreatic intraepithelial neoplasia
Feldmann, G., Beaty, R., Hruban, R. H., & Maitra, A. (2007) · Journal of Hepato-Biliary-Pancreatic Surgery · doi:10.1007/s00534-006-1166-5 · Cited by 269 · see citing works
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Update on pancreatic intraepithelial neoplasia.
Hruban, R. H., Maitra, A., & Goggins, M. (2008) · PubMed Central · Cited by 245 · see citing works
Self-citationPrasad, N. B., Biankin, A. V., Fukushima, N., Maitra, A., Dhara, S., ELKAHLOUN, A. G., Hruban, R. H., Goggins, M., & Leach, S. D. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-1413 · Cited by 240 · see citing works
Self-citationMolecular Pathogenesis of Pancreatic Cancer
Grant, T. J., Hua, K., & Singh, A. (2016) · Progress in Molecular Biology and Translational Science · doi:10.1016/bs.pmbts.2016.09.008 · Cited by 237 · see citing works
Pancreatic cancer microenvironment
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Precursor Lesions for Sporadic Pancreatic Cancer: PanIN, IPMN, and MCN
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MicroRNA Alterations of Pancreatic Intraepithelial Neoplasias
Yu, J., Li, A., Hong, S., Hruban, R. H., & Goggins, M. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2347 · Cited by 212 · see citing works
Self-citationMolecular pathogenesis of pancreatic cancer
Maitra, A., Kern, S. E., & Hruban, R. H. (2006) · Best Practice & Research Clinical Gastroenterology · doi:10.1016/j.bpg.2005.10.002 · Cited by 199 · see citing works
Self-citationTranscriptome analysis of microdissected pancreatic intraepithelial neoplastic lesions
Buchholz, M., Braun, M., Heidenblut, A., Kestler, H. A., Klöppel, G., Schmiegel, W., Hahn, S. A., Lüttges, J., Gress, T. M., & Krebshilfe, F. T. G. P. C. N. O. T. D. (2005) · Oncogene · doi:10.1038/sj.onc.1208804 · Cited by 190 · see citing works
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Self-citationMesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer
Li, M., Bharadwaj, U., Zhang, R., Zhang, S., Mu, H. H., Fisher, W. E., Brunicardi, F. C., Chen, C., & Yao, Q. C. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0483 · Cited by 178 · see citing works
Proteomic Analysis of Chronic Pancreatitis and Pancreatic Adenocarcinoma
Crnogorac‐Jurcevic, T., Gangeswaran, R., Bhakta, V., Capurso, G., Lattimore, S., Akada, M., Sunamura, M., Prime, W., Campbell, F., Brentnall, T. A., et al. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.08.012 · Cited by 170 · see citing works
Mucin expression profile in pancreatic cancer and the precursor lesions
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Pathology and Molecular Genetics of Pancreatic Neoplasms
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Self-citationHosoda, W., Chianchiano, P. E., Griffin, J. F., Pittman, M. E., Brosens, L. A. A., Noë, M., Yu, J., Shindo, K., Suenaga, M., Rezaee, N., et al. (2017) · The Journal of Pathology · doi:10.1002/path.4884 · Cited by 158 · see citing works
Self-citationBarriers and opportunities for gemcitabine in pancreatic cancer therapy
Beutel, A. K., & Halbrook, C. J. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00331.2022 · Cited by 150 · see citing works
Precursor Lesions of Pancreatic Cancer: Molecular Pathology and Clinical Implications
Singh, M., & Maitra, A. (2007) · Pancreatology · doi:10.1159/000101873 · Cited by 148 · see citing works
Self-citationSeki (2011) · International Journal of Oncology · doi:10.3892/ijo.2011.919 · Cited by 145 · see citing works
Genetically Engineered Mouse Models of Pancreatic Cancer
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Enhancing the Potency and Specificity of Engineered T Cells for Cancer Treatment
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Pancreatic Intraepithelial Neoplasia
Takaori, K., Hruban, R. H., Maitra, A., & Tanigawa, N. (2004) · Pancreas · doi:10.1097/00006676-200404000-00008 · Cited by 116 · see citing works
Self-citationCurrent Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions
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Self-citationPancreatic Intraepithelial Neoplasia Revisited and Updated
Sipos, B., Frank, S., Gress, T. M., Hahn, S. A., & Klöppel, G. (2008) · Pancreatology · doi:10.1159/000178874 · Cited by 112 · see citing works
Claudin-18 Is an Early-Stage Marker of Pancreatic Carcinogenesis
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Self-citationSMAD4 and its role in pancreatic cancer
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CEACAM6 Is a Novel Biomarker in Pancreatic Adenocarcinoma and PanIN Lesions
Duxbury, M. S., Matros, E., Clancy, T. E., Bailey, G., Doff, M., Zinner, M. J., Ashley, S. W., Maitra, A., Redston, M. S., & Whang, E. E. (2005) · Annals of Surgery · doi:10.1097/01.sla.0000154455.86404.e9 · Cited by 94 · see citing works
Self-citationPAM4-Reactive MUC1 Is a Biomarker for Early Pancreatic Adenocarcinoma
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Self-citationPharmacogenetics of anticancer drug sensitivity in pancreatic cancer
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Locally Advanced Pancreatic Cancer: A Review of Local Ablative Therapies
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Precursor lesions in pancreatic cancer: morphological and molecular pathology
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Molecular mechanism of pancreatic cancer—understanding proliferation, invasion, and metastasis
Mihaljević, A. L., Michalski, C. W., Friess, H., & Kleeff, J. H. (2010) · Langenbeck s Archives of Surgery · doi:10.1007/s00423-010-0622-5 · Cited by 81 · see citing works
Molecular Genetics of Pancreatic Neoplasms and Their Morphologic Correlates
Reid, M. D., Saka, B., Balcı, S., Goldblum, A., & Adsay, V. N. (2014) · American Journal of Clinical Pathology · doi:10.1309/ajcp0fkdp7envkev · Cited by 80 · see citing works
Fascin-1 expression in papillary and invasive urothelial carcinomas of the urinary bladder
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The Mdm network and its regulation of p53 activities: a rheostat of cancer risk
Eischen, C. M., & Lozano, G. (2014) · Human Mutation · doi:10.1002/humu.22524 · Cited by 79 · see citing works
Current and future biomarkers for pancreatic adenocarcinoma
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Circulating biomarkers for early diagnosis of pancreatic cancer: facts and hopes.
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Genetic Progression of Pancreatic Cancer
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Self-citationBiliary intraepithelial neoplasia in patients without chronic biliary disease
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Clinical importance of precursor lesions in the pancreas
Hruban, R. H., Takaori, K., Canto, M. I., Fishman, E. K., Campbell, K. A., Brune, K. A., Kern, S. E., & Goggins, M. (2007) · Journal of Hepato-Biliary-Pancreatic Surgery · doi:10.1007/s00534-006-1170-9 · Cited by 73 · see citing works
Self-citationHeterogeneity and Targeting of Pancreatic Cancer Stem Cells
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Self-citationMouse models of pancreatic cancer
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Deciphering the role of hedgehog signaling in pancreatic cancer
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Genetics and Biology of Pancreatic Ductal Adenocarcinoma
Dunne, R. F., & Hezel, A. F. (2015) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2015.04.003 · Cited by 67 · see citing works
Pharmacological activation of myosin II paralogs to correct cell mechanics defects
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- Authors
- Maitra, A., Adsay, N. V., Argani, P., Iacobuzio-Donahue, C., De Marzo, A., Cameron, J. L., Yeo, C. J., & Hruban, R. H.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Maitra, Anirban
- Venue
- Modern Pathology
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 16
- Issue
- 9
- Pages
- 902-912
- ISSN
- 0893-3952 (ISSN-L)
- OpenAlex
- W1980447806
- Cited by
- 429
- References
- 95
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 13 · 2023: 18 · 2022: 11 · 2021: 16 · 2020: 11 · 2019: 14 · 2018: 24 · 2017: 16 · 2016: 13 · 2015: 16 · 2014: 22 · 2013: 19 · 2012: 24
- FWCI
- 8.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Modern Pathology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P50CA-62924, P50CA062924)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
- Keywords
- pancreatic ductal adenocarcinoma, pancreatic intraepithelial neoplasia, tumor progression, precursor lesions, tissue microarray, molecular pathogenesis, p53, β-catenin, p16, cyclin D1, Ki-67, TOP2A, MUC1, MUC2, mesothelin, prostate stem cell antigen, fascin, 14-3-3 sigma, early detection
- MeSH terms
- Adenocarcinoma, Carcinoma in Situ, DNA, Neoplasm, Humans, Immunohistochemistry, Pancreatic Neoplasms, Precancerous Conditions, Biomarkers, Tumor, Disease Progression
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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